Integrative Cancer Science and Therapeutics

Review Article ISSN: 2056-4546

Translocations involving ETS family proteins in human cancer Elizabeth A Fry1, Ali Mallakin2 and Kazushi Inoue1* 1Department of Pathology, Wake Forest University School of Medicine, USA 2West Coast Biomedius, Canada

Abstract The ETS transcription factors regulate expression of involved in normal cell development, proliferation, differentiation, , and , consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating certain transcriptions. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. Three chimeric genes involving ETS genes have been identified in human cancers, which are EWS-FLI1 in Ewing’s sarcoma, TMPRSS2-ERG in prostate cancer, and ETV6-RUNX1 in acute lymphocytic . Although these fusion transcripts definitely contribute to the pathogenesis of the disease, the impact of these fusion transcripts on patients’ prognosis is highly controversial. In the present review, the roles of ETS protein translocations in human carcinogenesis are discussed.

Introduction translocation breakpoints in human and solid tumors [4-6]. Correlation of ETS levels with tumor progression has The v-Ets was discovered as a component of a chimeric been found in most human neoplasias, including leukemias, thyroid, gene, along with a truncated v-Myb gene, present in the genome of pancreas, liver, prostate, colon, lung, and breast cancers [2]. Aberrant E26, an avian leukosis virus [1-3]. Subsequently, v-Ets-related genes expression of ETS1 and 2 proteins results in the altered regulation of have been identified from different species. The Ets family has been their target response genes, which was recently reviewed [4-6]. established as one of the largest group of transcriptional factors, with diverse functions [2, 3]. To date, 28 human ETS family proteins have The ETS transcriptions factors regulate numerous genes by been identified [3-5]. All ETS genes have a conserved amino acid binding to GGAA/T core of DNA-binding, and are involved in stem sequence (the ETS domain) of approximately 85 amino acids that cell development, cell proliferation, differentiation, development, forms the DNA-binding domain at the C-terminus required for the transformation, angiogenesis, and apoptosis (Figure 1) [7]. ETS1 and recognition of the consensus core sequence GGAA/T (ETS binding site ETS2 are representative members of the ETS family of transcription [EBS]) (Figure 1B). Binding of ETS proteins to target genes is accelerated factors and are downstream effectors of the RAS/RAF/ERK pathway, by the binding of other trans-acting factors to close proximity to the which involve in cellular proliferation, differentiation, apoptosis and EBS. The pointed (PNT) domain of 65–85 amino acids is the second transformation [7]. most conserved region found in a subset of ETS genes (Figure 1). This domain is found in 11 of 28 human ETS genes and has been shown It was reported that the ETS2 gene was located approximately 17 cM to participate in protein-protein interaction and oligomerization [3-5]. from the breakpoint of common t(8;21) translocation of M2 subtype of The human ETS factors are classified into 11 subgroups: ETS (ETS1/2), acute myelogenous leukemia (AML) [8, 9]. They demonstrated that ERG, FLI1, ETV (PEA3, ETV1/4/5), TEL (ETV6/7), ELG (GABPα), ERG was situated just proximal to ETS2. However, AML1/ETO was TCF (ELK1/3/4), ELF (ELF1/2/4), SPI1 (SPI1/B/C), ERF (ERF, ETV3, cloned and shown to be responsible for t(8;21) in acute myelogenous ETV3L), and FEV (Figure 1) [4]. In addition, a subset of four ETS family leukemias [10,11]. Rao et al. performed in situ hybridization and genes (ELF3, ELF5, EHF, SPDEF) has been placenta-specific subgroup somatic cell hybridization that the ERG gene is located at based upon their restricted expression to tissues with high epithelial 21q22.3 [12,13]. They found that the ERG gene was translocated from cell content (4-6); there are total of 28 ETS proteins in humans [4,5]. chromosome 21 to chromosome 8 in the t(8;21)(q22;q22). It was then found that ERG2 is a nuclear phosphoprotein that bound to purine- ETS factors are regulators of the expression of genes that are rich sequences [14]. ERG is considerably more stable than the short- involved in various biological processes in response to various signaling cascades, cellular proliferation, differentiation, apoptosis, migration, invasion/metastasis [7]. They also control cell adhesion, *Correspondence to: Kazushi Inoue, Department of Pathology, Wake Forest tissue remodeling, extracellular matrix composition, and angiogenesis University School of Medicine, Medical Center Blvd., Winston-Salem, NC [7]. ETS protein functional activity is modulated by post-translational 27157, USA, Tel: +1-336-407-1642, Fax: +1-336-765-2486, E-mail: kinoue2@ modification and interaction with other nuclear proteins. The triad.rr.com importance of ETS genes in human carcinogenesis is supported by the observations that ETS genes have altered expression patterns, Key words: ETS, ERG, EWS, FLI1, TMPRSS2, ETV6, RUNX1 expression, cancer amplified, deleted mutated, and most importantly are located at Received: June 28, 2018; Accepted: July 16, 2018; Published: July 20, 2018

Integr Cancer Sci Therap, 2018 doi: 10.15761/ICST.1000281 Volume 5(4): 1-12 Fry EA (2018) Translocations involving ETS family proteins in human cancer

PNT TAD Id ETS Id ETS

ERG

Fli1

ETV

TEL RD ELG

TCF

ELF

SPI1

ERF

Figure 1. The structure of ETS family proteins The structure of ETS family proteins. The human ETS factors are classified into 11 subgroups: ETS (ETS1/2), ERG, FLI1, ETV (PEA3, ETV1/4/5), TEL (ETV6/7), ELG (GABPα), TCF (ELK1/3/4), ELF (ELF1/2/4), SPI1 (SPI1/B/C), ERF (ERF, ETV3, ETV3L), and FEV [4,5,165,166]. There are totally 28 ETS proteins in humans. ETS translocations involving Fli1, ERG, and TEL have been discussed in this review. The ETS domain that is essential for DNA-binding is shown in dark box. The DNA-binding by the ternary complex factor (TCF) subfamily of ETS-domain transcription factors is tightly regulated by intramolecular and intermolecular interactions [167-169]. The helix-loop-helix (HLH) - containing Id proteins are trans-acting negative regulators of DNA binding by the TCFs. Id domains have been identified in ETS, ETV, and TCF. PNT: pointed domain, TAD: transactivation domain, ID: Id-interaction domain, ETS: ETS domain (DNA-binding domain), RD: ring domain. lived ETS1 and ETS2 proteins with a half-life of 21 hours [7]. ERG2 is sequencing analysis, the same group identified 2 different ERG a sequence-specific, DNA-binding protein and is expressed at higher transcripts, ERG1 and ERG2. ERG2 differs from ERG1 by a splicing levels in early myeloid cells than in mature lymphoid cells, acting as a event that causes a frameshift, resulting in an additional 99 amino acids regulator of genes required for maintenance and differentiation of early at the N terminus [22]. They found that alternative sites of splicing hematopoietic cells. and polyadenylation, together with alternative sites of translation initiation, allow synthesis of 2 ERG polypeptides, ERG1 and ERG2. The ETS family gene often fuses with other genes as a result of Then Owczarek et al. reported that 5 alternatively spliced ERG translocation. The ERG gene is found at the breakpoint of t(16;21) transcripts encode proteins of 38 to 55 kD, all of which bind to ETS (p11;q22) in the FUS:ERG fusion in leukemia [15]. In solid tumors, the sites of genomic DNA and acted as transcriptional factors [23]. RT- ERG gene is activated by translocation in Ewing sarcoma with EWS:ERG PCR analysis of 6 ERG variants showed variable expression in placenta translocation t(11;22)(q24,q22) [16] and EWS:FLI1 translocation t(21,22) and most human cell lines examined. They found that theERG gene (q22,q12) (Fli1 belongs to ERG family of proteins) (Figure 1B) [4]. contained at least 17 exons that have extension of >280 kb. It has been reported that the TMPRSS-ERG translocation is found in 50% of prostate cancer (PCa), and is associated with prognosis EWS:ERG in Ewing sarcoma (Figure 1B) [17-19]. Studies suggest the involvement of another The ERG gene often fuses with others as a result of translocation member of the ETS family, known as ETV6, in human cancer. ETV6 as described earlier. Ichikawa et al. demonstrated that in human is frequently activated in human leukemia with ETV6-RUNX1 (TEL- myeloid leukemia with t(16;21)(p11;q22), the TLS/FUS gene on AML1) [20,21]. The roles of these ETS proteins in causing human chromosome 16 was fused with ERG gene on chromosome 21 [24]. cancer, especially acute leukemia, Ewing’s sarcoma, and PCa are The chimericFUS:ERG gene product is an DNA-binding protein that discussed in this review. was highly homologous to the product of the EWS gene involved in ERG Ewing sarcoma. FUS and EWS are homologous to each other. Thus, the FUS:ERG gene fusion found in t(16;21) leukemia was predicted to Gene cloning and expression produce a protein similar to the EWS:ERG chimeric protein seen in Ewing’s sarcoma. The Reddy’s group isolated a cDNA that comes with the complete coding sequence of ERG and predicted 363-residue protein. They Ewing sarcoma, the second most common malignant bone tumor predicted that ERG share about 40% and 70% homology with the 5’ of children and young adults, is an aggressive osteolytic tumor with and 3’ regions of the v-Ets oncogene, respectively, suggesting that a marked propensity for dissemination to the bones (arms, ribs, ERG belongs to the ETS oncogene family (Figure 1B) [22]. Through legs, pelvis), lungs, spine, and [25-27]. It belongs to

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the heterogeneous group of small round cell tumors that are often a expression and to modulate the transformed of Ewing diagnostic challenge to the pathologist and clinical oncologist. EWS sarcoma [40,41]. Other known direct transcriptional targets of EWS- and related peripheral primitive neuro-ectodermal tumors show a FLI1 are glutathione-S-transferase M4, protein tyrosine phosphatase t(11;22)(q24,q22) translocation (present in 85% of Ewing’s sarcoma; L1 (PTPL1), GLI1, and AP1 [42-44]. Similar to the inhibition of PTPL1, EWS-FLI1 fusion) [28] or a t(21,22)(q22,q12) (EWS-ERG fusion) that pharmacological inhibition of GLI1 decreased proliferation and soft is associated with hybrid transcripts of the EWS gene with the FLI1 agar colonies in Ewing sarcoma family tumor (ESFT) cells. In many or ERG gene [29]. The chimeric protein resulting from the fusion of cases, however, pathogenesis of EWS-FLI1 depends on cooperative EWS with ERG is structurally similar to the typical EWS-FLI1 protein DNA-binding with other transcription factors, such as AP1, which have in which the N-terminal portion of EWS is linked to the ETS domain tandem binding sites close to the EWS-FLI1 target promoters [45]. of ERG (Figures 1 and 2) [29-33]; Upon fusion, EWS-FLI1 becomes Pathogenesis of Ewing’s sarcoma also depends on other genetic a more potent transactivator than FLI1 itself although it does not alterations or cellular functions that indirectly control EWS-FLI1 transactivate the Arf [35]. It has been reported that many activity. Among these functions are the and RB pathways, hypoxia, targets of EWS-FLI1, both direct and indirect, have been found to be IGF1/IGF1R signaling, and microRNAs [46]. Loss of tumor suppressor involved in Ewing sarcoma maintenance [33]. EWS-FLI1 collaborates genes, such as p53 [47,48] or Ink4a/ARF [49,50], greatly accelerate with several proteins to modulate mRNA transcription and splicing tumorigenesis in EWS-FLI1-transgenic mice [51,52], and studies (Figure 2) [29-33]. Biochemical and computer studies have revealed have shown that loss of p16Ink4a stabilizes EWS-FLI1 expression and that the EWS-FLI1 molecule is intrinsically disordered, from the cooperates with EWS-FLI1-mediated transformation [53]. Although amino-terminus of EWS to the DNA-binding domain of FLI1, and EWS-FLI1 recognizes the ETS sequence on the Arf promoter, it does that unique side chains within a structure of EWS-FLI1 are critical for not affect the Arf transcription like the Myb-like protein DMP1 the transcription and transforming activity of the EWS family proteins [35,37,54-73]. These data indicate that p16Ink4a is the target in the (Figure 2) [34]. Interestingly it was reported that EWS-FLI1 employs pathogenesis of EWS. In ESFT, hypoxia has been shown to contribute an switch to drive target gene expression [35-39]. The Bayesian to resistance of apoptosis via HIF1α [74]. EWS-FLI1 expression model (a theory in the field of statistics in which the evidence about increases transiently under hypoxic conditions in a HIF1α-dependent the true state of the world is expressed in terms of degrees of belief) manner; colocalization of HIF1α and necrotic areas in an ESFT tissue revealed that the formation of a synergistic complex between EWS- array has been reported [74]. FLI1 and was the most likely mechanism explaining the observed Transgenic mouse models have shown their ability to closely kinetics of E2F target induction [36]. They proposed that aberrant cell reproduce the conditions of transgenes in mice [75,76]. However, no cycle activation in EWS was due to the physical recruitment of E2F3 by genetically engineered mouse models (GEMM) have been created for EWS-FLI1 replacing on their target promoters [36]. Ewing’s sarcoma so far because transgenic expression of the EWS- A direct transcriptional target of EWS-FLI1 is NROB1/DAX1 Fl1 fusion gene causes embryonic lethality [52]. The differences in and it is a key effector in EWS-FLI1-mediated oncogenesis [40]. signaling pathways, Ets-binding sites, co-regulators between mice siRNA-mediated depletion of DAX1 in EWS-FLI1 cell lines results in and humans mice cause additional issues. To make GEMM for EWS, growth arrest and inhibition of tumor formation in immunodeficient EWS-FLI1 should be expressed exclusively in mesenchymal stem cells mice. DAX1 also physically interacts with EWS-FLI1 to control gene (MSCs) to avoid its expression in hematological tissues [77]. Torchia et

EWS TA RNA-binding

exons 1-4 exons 5-7 exons 8-10 exons 11-13 exons 14-17

FLI1 ETS/DBD TA

Exons 1-3 Exon 4 5 6 7 8 9

EWS-FLI1 ETS/DBD TA

exons 1-4 exons 5-7 variable

Figure 2. The EWS-FlI1 chimeric gene found in Ewing’s sarcomas The EWS-FlI1 chimeric gene is found in 80% of Ewing sarcomas. Vertical arrow shows the major breakpoints (between exon 7 and 8 in EWS gene and exons 5 and 6 in ETS-like FLI1 gene). The thin arrows represent the minor breakpoints. The EWS-FLI1 gene is a fusion between EWS and FLI1, transactivation (EWS) and DNA-binding (FLI1) domains. The structure between EWS and FLI1 varies dependent on the Ewing’s sarcoma.

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al. therefore took an approach to express EWS-FLI1 in mesenchymal TMPRSS2-ERG fusion gene in prostate cancer (PCa) tissues. They created mice with Cre-inducible expression of EWS-FLI1 from the ubiquitous Rosa26 [78]. When crossed with Mx1-Cre By using a bioinformatics approach (Figure 3), Tomlins et al. mice (interferon-inducible the most commonly used “deleter strain” in [81,82] reported candidate oncogenic chromosomal aberrations in experimental that is interferon-inducible) [79], activation PCa. Two ETS transcription factors, ERG and ETV1, were identified of EWS-FLI1 resulted in the rapid development of myeloid/erythroid (Figure 1). They demonstrated that 23 of 29 PCa samples (79%) had leukemia characterized by expansion of primitive mononuclear cells rearrangements in ERG or ETV1 by FISH. Later experiments have causing hepatosplenomegaly, severe , and death [78]. Gene shown that the TMPRSS2-ERG translocation was found in ~50% of expression profiles of primary and transplanted animals were highly Caucasians, with a lower frequency in African Americans, and even similar, suggesting that activation of EWS-FLI1 was the primary less common in Asians [83]. Cell line experiments suggested that the event leading to disease in this model. The Cre-inducible EWS-FLI1 androgen-responsive promoter elements of TMPRSS2 mediate the mice provided a novel model system to study the contribution of this overexpression of ETS family members in PCa [81]. Using chromatin oncogene to malignant disease in vivo [78]. immunoprecipitation coupled with sequencing, Yu et al. found that ERG disrupts androgen (AR) signaling by inhibiting The Lozano lab created conditional transgenic GEMM for Ewing’s AR expression, binding to and inhibiting AR activity, and inducing sarcoma by inducing EWS-FLI1 expression in the primitive MSC of repressive epigenetic programs via direct activation of the H3K27 the embryonic limb buds by making use of specific recombinases that methyltransferase EZH2 [84]. In normal tissues, the TMPRSS2 and allow spatio-temporal control of the EWS-FLI1 gene (EF mice) [52]. ERG genes are localized tandemly on chromosome 21q22 (Figure 3) When crossed to the Prx1-Cre transgenic mouse, which expresses Cre [81]. The TMPRSS2-ERG fusion joins TMPRSS2 exons 1 or 2 to ERG recombinase in the primitive mesenchymal cells of the embryonic limb exons 2, 3, or 4, which results in activation of the ERG transcription bud, the EF mice had number of developmental defects of the limbs factor [81,85]. [52]. These included shortening of the limbs, muscle atrophy, cartilage dysplasia, and immature bone. Under the condition of p53 deletion, The mechanism of translocation was studied by Mani et al. [86]. By EWS-FLI1 accelerated the formation of sarcomas from a median time studying human PCa cells with fluorescence in situ hybridization, they of 50 to 21 weeks, with poorly differentiated phenotype [52]. Taken showed that androgen signaling induces proximity of the TMPRSS2 together, the results suggest that EWS-FLI1 inhibits normal limb and ERG genomic loci, both located on chromosome 21q22.2 (Figure development and accelerates the formation of poorly differentiated 3). Subsequent exposure of the cells to γ-irradiation, which causes DNA sarcomas. double-strand breaks, facilitates the formation of the TMPRSS2-ERG gene fusion. Their results explain why TMPRSS2-ERG gene fusions are One important issue we have to remember to reproduce Ewing’s restricted to the prostate, which is dependent on androgen signaling [86]. sarcoma in GEMM is the influence of the reciprocal chimeric protein FLI1-EWS generated from the locus [80]. Elzi et al. reported that FLI1- Transgenic models for TMPRSS2-ERG gene fusion in EWS was frequently expressed in Ewing’s sarcoma and presented mice evidence that endogenous FLI1-EWS was required for Ewing’s sarcoma growth, and that it cooperated with EWS-FLI1 in human Tomlins et al. [87] studied the role of TMPRSS2-ERG gene fusion mesenchymal stem cells through abrogation of the proliferation arrest product using in vitro and in vivo model systems. Transgenic mice induced by EWS-FLI1. Thus, creation of double transgenic GEMM for expressing the ERG gene fusion product under androgen-regulation EWS-FLI1 and FLI1-EWS under specific promoter might be necessary developed PIN. Introduction of the ERG gene fusion product into to reproduce Ewing’s sarcoma [80]. primary or immortalized benign prostate epithelial cells induced an

Chromosome 21

21q22.3 21q22.2 21q22.11 21q21.3 21q21.1 21p12

TMPRSS2 ERG

1 2 3 4-13 14 1 2 3 4 5-10 11

TMPRSS2:ERG 1 4 5-10 11 Figure 3. The TMPRSS2-ERG gene found in prostate cancer The TMPRSS2-ERG or ETV chimeric gene has been found in ~80% of prostate cancer samples of radical prostatectomy [81]. The former translocation has been found in ~50% of Caucasians, with a lower frequency in African Americans, and even less common in Asians [83]. The structure of chromosome of 21 where the chimeric gene for TMPRSS2-ERG is derived is shown. Most of the resultant TMPRSS2-ERG gene consists of exon 1 of TMPRSS2 (non-coding) and exons 4-11 of ERG indicating that the gene makes near full-length proteins of ERG consistent with ERG overexpression in PCa. On the other hand, the TMPRSS2-ETV1 fusion results in chimeric protein that consists with a part of TMPRSS2 and truncated form of ETV1, resulting in expression of the that is not expressed in normal tissues

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invasion-associated transcriptional program, but did not increase in frame fused with exon 4 of the ERG gene, was associated with clinical cellular proliferation or anchorage-independent growth [87]. ERG and pathologic manifestations of aggressive disease [93]. Expression of knockdown in VCaP cells (PCa cell line established from a vertebral other isoforms, in which the native ERG ATG in exon 3 was used, was metastatic lesion) induced a transcriptional program consistent with associated with seminal vesicle invasion with poor outcome following prostate differentiation [87]. Importantly, VCaP cells and benign radical prostatectomy [93]. Cancers not expressing these isoforms prostate cells overexpressing ERG directly engage components of expressed higher levels of fusion mRNAs, which was present in PCa the plasminogen activation pathway to mediate cellular invasion, with early prostate-specific antigen recurrence. Thus, both isoforms of potentially representing a downstream ETS target susceptible to TMPRSS2-ERG fusions expressed and expression levels might affect therapeutic intervention. Thus, TMPRSS2-ERG fusions mediate PCa progression with poor prognosis [93]. Further studies are needed invasion, consistent with the histologic distinction between PIN and to elucidate the roles of the known and variant ERG fusions in the PCa [87]. pathogenesis and androgen dependency of PCa. Carver et al. [88] reported that aberrant expression of ERG is Aberrant TMPRSS2-ERG signaling in PCa a progression event in prostate tumorigenesis. Interestingly, PCa specimens containing the TMPRSS2-ERG rearrangement were It has been reported that increased expression of ETS proteins in significantly enriched for loss of the tumor suppressor PTEN, consistent adult murine prostate epithelial cells is sufficient to induce epithelial with the report by King et al. [89]. Similarly, transgenic overexpression hyperplasia and focal prostatic PIN lesions, but not enough in of ERG in mouse prostate tissue promotes marked acceleration and progression to carcinoma [94,95], which are consistent with the progression of high-grade prostatic PIN to prostatic adenocarcinoma findings by Tomlins et al. for the fusion protein PCa [81,82]. ERG in a Pten-heterozygous background [88]. In vitro overexpression of interacts with activations in PI3K signaling, such as PTEN inhibition or ERG promotes cell migration, a property necessary for tumorigenesis, AKT1 upregulation, to cause the development of a well-differentiated without affecting proliferation. They showed that ADAMTS1 and adenocarcinoma. Thus, loss of PTEN and the presence of the TMPRSS2-ERG gene fusion are events significantly associated with CXCR4, two candidate genes strongly associated with cell migration, PCa [96]. Bismar et al. proposed the hypothesis that PCa development were upregulated in the presence of ERG overexpression [88]. Thus, might be driven initially by PTEN hemizygous loss that caused high ERG has a distinct role in PCa progression and cooperates with PTEN grade PIN lesions, which leads to genomic instability, chromosomal haploinsufficiency to promote progression of high grade PIN to rearrangement, and progression to cancer [97]. Subsequent biallelic invasive adenocarcinoma. PTEN inactivation characterizes a particularly aggressive subset of Recently, Mounir et al. compared the transcriptional effects of metastatic and hormone-refractory PCa [98]. HDAC1 upregulation is TMPRSS2-ERG expression in a transgenic mouse model [90]. ERG common in PCa, and was found to be increased in tumors with ERG repressed the expression of a previously unreported set of androgen rearrangement [99]. ERG overexpression in PCa is highly implicated receptor (AR)-independent neuronal genes that were indicative of in promoting motility and invasiveness, high levels of HDAC1, and neuroendocrine (NE) cell differentiation. Cell sorting and proliferation subsequent down-regulation of HDAC1-targeted genes, activation assays performed after ERG knockdown indicated that ERG drove of WNT/β-catenin signaling pathway, and inhibition of apoptosis. proliferation and blocked the differentiation of prostate cells to both Activation of the AR through the WNT/β-catenin signaling results NE and luminal cell types [90]. They also provided evidence that these in increase in AR expression, enhanced transcription of TMPRSS2- NE cells were resistant to pharmacological AR inhibition, and can ERG, and high levels of ERG [100]. Elevated ERG, in turn, modulates revert to the phenotype of parental cells upon restoration of AR/ERG the growth of PCa cells by upregulating the oncogene, and by signaling. Thus ERG may have a direct role in preventing resistance to abrogating the differentiation of prostate epithelium [101]. Elevated anti-androgen therapy [90]. MYC expression in primary PCa is biologically relevant and may be a predictor of future biochemical recurrence [102]. In summary, Expression of the TMPRSS2-ERG fusion protein in PCa activation of the HDAC1-WNT/β-catenin-MYC pathway by ERG arrangement is associated with invasive behavior in PCa [103,104]. Although the TMPRSS2 (chr 21q22.3, exon 1) - ERG (chr 21q22.2, exon 4) fusion with intra-chromosomal deletion of 3MB on TMPRSS2-ERG gene fusion as a prognostic marker for chromosome 21 is quite common (Figure 3), other expressed variants PCa have been reported [91,92] differing in the exon break points in TMPRSS2 (exons 1-5) and ERG (exons 2-5). Depending on the exon The prognostic implications of TMPRSS2-ERG fusion gene in PCa break point, protein translation is predicted to start either (1) at the have not been established. Some authors found a correlation between genuine ATG of ERG (exon 3), (2) the native ATG of TMPRSS2 (exon the presence of fusion gene/protein and poor prognosis [92,93,105- 2), or (3) an in-frame ATG within exon 4 or 5 of ERG; in the third 110], but others found a correlation with good prognosis [111-113], the cases the N terminus of ERG would be truncated (Figure 3). This is third group reported no correlation with prognosis of PCa [114-117]. important since the expression of selected TMPRSS2-ERG break point In the first group, Attard et al. reported that patients with two or variants has recently been linked to specific clinicopathological features more copies of the TMPRSS2-ERG fusion gene due to the interstitial of PCas. deletion had worse survival rates than patients without TMPRSS2- Wang et al. [93] reported that the expression of TMPRSS2-ERG ERG rearrangement [106]. This is consistent with the view that ERG fusion mRNAs and correlated the isoforms expressed and expression overexpression is responsible for driving cancer progression [118], levels with clinical outcome in cancers from men undergoing radical and that the 2.8 Mb deletion (containing genes with tumor suppressor prostatectomy. Overall, 59% of clinically localized PCas expressed the activity) may contribute to the oncogenic potential of the TMPRSS2- TMPRSS2-ERG fusion gene, confirming the initial observations of ERG fusion product [81]. To understand molecular signatures high frequency expression of this mRNA in PCa [81]. Expression of an associated with poor outcome in PCa, Markert et al. [107] analyzed isoform, in which the native ATG in exon 2 of the TMPRSS2 gene was a microarray data set characterizing 281 PCa from a Swedish cohort.

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They identified a subset of tumors manifesting stem-like signatures also been reported that TMPRSS2-ERG gene fusion was not associated together with p53 and PTEN inactivation, which had very poor survival with PCa recurrence, but that ERG gene copy number gain without outcome; a second group characterized by the TMPRSS2-ERG fusion fusion was associated with twice the risk of PCa recurrence [116, 117]. with poor survival outcome, composed of 18% of the tumors in the They explained that the ERG gene copy number increase in PCa was the dataset [107]. Font-Tello et al. reported that the expression levels of result of tumor aneuploidy, which potentially leads to chromosome 21 the TMPRSS2-ERG fusion and ERG mRNA were associated with high polysomy [118]. In this context, the association of greater probability of Gleason scores, aggressive PCa , low PTEN expression, tumor progression with increased copy number of the ERG gene formed and poor prognosis [108,109]. Finally Deplus et al. reported that without fusion is not surprising given the previous evidence supporting TMPRSS2-ERG increased bone tropism of PCa cells and metastasis aneuploidy as a negative prognostic indicator in PCa [119, 120]. development [110]. Overall, these results suggest that TMPRSS2-ERG It seems that early studies tended to interpret TMPRSS2-ERG could be molecular markers of aggressiveness for PCa. gene fusion as a marker of poor prognosis; however, later large cohort In the second group, Saramäki et al. [111] studied the presence of studies report that it is a marker of better prognosis. There are several the TMPRSS2-ERG rearrangement by reverse transcription-PCR and explanations for the different prognostic values of TMPRSS2-ERG: fluorescence in situ hybridization in 19 PCa xenografts and 7 PCa they are clinical settings, size of patient cohorts, differences in sample cell lines. The expression of ERG was studied in the xenografts, cell collection, and the technique used for determination of fusion gene. lines, and in 49 freshly frozen clinical prostate samples by quantitative It is generally believed that high expression of TMPRSS2-ERG fusion reverse transcription-PCR. Seven of 19 (37%) of the xenografts transcript in PCa tumor tissue in combination of high PSA and low overexpressed ERG and had TMPRSS2-ERG rearrangement. In clinical PTEN levels are associated with aggressiveness of the tumor with poor tumor specimens, the overexpression of ERG was associated with the prognosis. rearrangement. Fifty of 150 (33%) of the prostatectomy specimens and 28 of 76 (37%) of the hormone-refractory PCa on tissue microarrays ETV6-RUNX1 (TEL-AML1 ) in human leukemia carried the TMPRSS2-ERG rearrangement [111]. It was associated with Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy longer progression-free survival in patients treated by prostatectomy, characterized by clonal proliferation of immature blood cell precursors and was an independent predictor of favorable outcome. The fusion (blasts) that progresses rapidly into systemic disease. Signs of leukemia was not associated with other clinical markers such as Gleason score, include fever and hemorrhage caused by reduced number of . clinical stage, prostate-specific antigen. In pediatric B-cell ALL, the most frequent chromosomal lesion is In the third group, Gopalan et al. [115] analyzed TMPRSS2-ERG t(12;21)(p13;q22), which results in the fusion of ETV6/RUNX1 (E/R gene rearrangement status by fluorescence in situ hybridization in 521 fusion; also known as TEL/AML1) fusion gene (Figure 4) [121-123]. cases of clinically localized surgically treated PCa with 95 months of This genetic alteration occurs in ~25% of pediatric ALL diagnosed median follow-up. 42% of primary tumors and 40% of metastases had between the ages of 2 and 10 years [123,124]. It was originally believed rearrangements. 11% had copy number increase of the TMPRRS2- that this rearrangement is a favorable prognostic indicator based on ERG region. Rearrangement alone was associated with lower grade, the excellent molecular response to treatment and beneficial clinical but not with stage, biochemical recurrence, metastases, or survival. outcome [125-127]. However, others found late relapses occurring in They reported that a subgroup of cancers with chromosomal number up to 20% of patients [128,129], suggesting that it is a sign of ominous instability (CNI) and rearrangement by deletion, with two or more prognosis in some patients. copies of the deleted locus, tended to be more clinically aggressive. The E/R fusion gene develops as an early event in childhood ALL. DNA index assessment revealed that the majority of tumors with The expression of E/R results in generation of a persistent pre-leukemic CNI of TMPRSS2-ERG had generalized aneuploidy/tetraploidy in clone, which postnatally changes to ALL after secondary genetic events comparison to control tumors. They concluded that translocation of [129]. The detection of the E/R fusion sequence in identical twins and TMPRSS2-ERG was not associated with clinical outcome [115]. It has pediatric ALL indicates that this gene fusion happens in the prenatal

exon 1A 2 1B 3 5 7

5’ 3’

telomere centromere TEL, ~350kb, 12p13

exon 8 7B 7A 6 4 2

3’ 5’

centromere telomere AML1, ~500kb, 21q22

Figure 4. The genomic DNA structure for the TEL-AML1 (ETV6-RUNX1) locus Translocations involving these loci are found in 25% of pediatric ALL, and are associated with relatively favorable prognosis. The TEL (ETV6) gene is chromosome 12p13, and the AML1 (RUNX1) gene is located on chromosome 21q22. The shaded boxes indicate the locations of breakpoints found in ALL. “The numbers are the positions of exons. The breakpoints comes from references 168 and 169. The intron 2 in reference 168 is intron 1 in reference 169.”

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period [130]. However, 1) the occurrence of ALL simultaneously is [146,147]. Many practitioners adopt therapeutic found in only 5% of twin children, 2) the postnatal latency period of the strategies involving risk-adapted treatment, alternating short term disease is highly variable, and 3) data from transgenic animal models chemotherapy, in some cases together with cranial/craniospinal of E/R fusion [131] suggest that additional genetic events are required irradiation, and conventional maintenance therapy [146]. Salvage for the development of overt ALL. Early studies addressing secondary treatment after ALL relapse involves inducing a second remission genetic changes have focused on the deletion of the non-rearranged with conventional intensive chemotherapy and consolidation, re- ETV6 allele which is a tumor suppressor by dimerizing with E/R to intensification and maintenance therapy, or allogeneic stem-cell reduce its transforming activity [132,133]. Consistently, loss of ETV6 transplantation (SCT) to strengthen a treatment [148]. Effective is found in as many as 70% of t(12;21) (+) ALLs [134,135]. Moreover, treatment of ALL relapse very much depends on the risk-based ~20% of t(12;21) (+) patients have additional genetic change in ETV6 treatment allocation of patients in order to maximize response or RUNX1 [136]. These genomic changes are so common that ETV6 to therapy while minimizing toxicity and adverse effects from has been attributed to the development of E/R(+) ALLs. chemotherapy [146-148]. Using the prognostic factors such as first remission duration; site and immunophenotype of relapse; To understand the genetic evolution of E/R(+) ALL without genetic alterations; and initial response to relapse therapy, distinct prejudice, identification of entire spectrum of genetic changes that subgroups of relapsed ALL can be identified, which may either accompany this fusion gene is necessary. The genome of E/R (+) ALL be treated with chemo and radiation therapies or by additional has been well-characterized at the copy number and cytogenetic level. allogeneic steam cell treatment [149]. Since responses to single Generally, E/R (+) ALL has an average of 2.8 (0-14) additional copy agent therapy have been poor, integrating new chemotherapy number alterations (CNAs) [137]. As predicted, deletion of 12p (39%) agents in combination with novel approaches, new antimetabolites, was the most common abnormality resulting in the loss of wild type and monoclonal antibodies against leukemia-associated antigens ETV6 allele [138]. The 9p deletion containing the INK4b/ARF/INK4a can been implemented [150,151]. locus [139-141] can be seen in up to 25% of E/R(+) patients, and the B-cell differentiation regulatorPAX5 [126,142]. CDKN2a/b, ETV6, Molecular mechanisms and the treatment of E/R(+) PAX5, deletions, chromosome 6q loss, and chromosome 16 gain are ALL in relapse probably among the earliest genetic aberrations in E/R(+) ALL [143]. Fuka et al. addressed the issue by conducting a shRNA-mediated knock- In most E/R patients, relapses occur several years after down (KD) of the E/R fusion gene and investigated the consequences discontinuation of treatment meaning that relapse is a genetic with two E/R(+) leukemic cell lines [144]. Microarray analyses alterations [125-129]. To characterize the clonal origins of E/R(+) identified 777 genes whose expression was significantly altered. The ALL relapse, numerous studies have compared immunoglobulin/T cell E/R KD - upregulated set was enriched for genes included in the “cell receptor gene rearrangements, genomic structure of un-rearranged activation”, “apoptosis”, “signal transduction”, “immune response”, ETV6 allele, and CNA patterns of diagnostic and relapse samples in and “development and differentiation” categories, whereas in the E/R the same patient [152-155]. Most importantly, late relapsing cases of KD - downregulated set consisted only with the “PI3K/AKT/mTOR E/R(+) ALL are chemosensitive with long-term remissions, implying signaling” and “hematopoietic stem cells”, which was confirmed with that initial survival and re-emergence have common properties primary E/R(+) ALL samples [144]. The results suggest that the E/R [156]. Comparison of genomic boundaries of un-rearranged ETV6 chimeric protein accelerates tumorigenesis by up-regulating genes allele indicated that the relapse clone derived from a sibling clone involved in cell proliferation without sending signals to the PI3K-AKT- already present at diagnosis [153,154]. It is possible that this minor mTOR pathway. population shows only moderate reduction during initial therapy, but rapidly expands before relapse. After relapse, these clones are rapidly Pathogenesis, diagnosis, and treatment of ALL in re- eradicated by chemotherapy [152]. In conclusion, the relapse clones lapse of E/R(+) leukemia originate from those exist at initial presentation. Then what is the impact of E/R fusion in patients’ responsiveness Most ALL relapses occur during treatment, following to therapy? To gain insight into the relapse mechanisms, Kuster et al. discontinuation of treatment or within the first 2-year after treatment [157] analyzed single nucleotide polymorphism arrays for CNAs in 18 completion. Certain relapses have been reported to occur even after matched diagnosis and relapse ALLs. They identified recurrent, mainly longer period of time following the initial diagnosis [125-129,145]. Site non-overlapping deletions associated with glucocorticoid-mediated of relapse and length of first remission are the major criteria for the apoptosis targeting the Bcl2 modifying factor (BMF), glucocorticoid classification of patients after first relapse, which include patients with receptor NR3C1, and components of the mismatch repair pathways isolated or concurrent marrow, isolated central (CNS), [157]. Fluorescence in situ hybridization demonstrated that BMF isolated testicular and other extramedullary relapses with or without deletions, NR3C1 and mismatch repair alterations became more CNS involvement [145]. Leukemia relapse is the result of outgrowth of common at relapse. These findings implicate that glucocorticoid- a clonal cell population not entirely eradicated by treatment. Each case associated drug resistance in E/R(+) relapse, which is a direction for of ALL comprises of a unique rearrangement of immunoglobulin or future therapies. T-cell receptor (TCR) genes; therefore, detailed study on rearrangements of immunoglobulin or TCR genes typical of ALL clones may help to Gandemer et al. performed a long-term, follow-up retrospective determine the origin of leukemia recurrence. Origin of the relapsed study to address the outcome of patients with E/R(+) leukemia relapses ALL has been addressed based on the study of genome-wide DNA copy [158]. They reported that E/R had a strong effect on overall survival number analysis on matched samples obtained at the time of diagnosis after relapse. In 81% of cases the relapses that were found late, they and relapse [146]. were combined with extramedullary relapses. The 5-year survival rate of patients with E/R(+) ALL relapses reached 81% when the relapse Standard recovery regimens for relapsed ALL are typically based occurred after 36 months [158]. In multivariate analysis, only the on different combinations of the same agents used in frontline duration of first remission remained associated with outcome. Overall,

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they found an excellent outcome for patients with E/R(+) leukemia Conflicts of Interest relapses that occurred more than 36 months after diagnosis [158]. The duration of first complete remission may be a guide to define the The authors declare no conflicts of interest. treatment strategy for patients with relapsed E/R(+) leukemia. Similar Author contributions findings were reported by other groups [159-163], demonstrating that E/R fusion is a sign of favorable prognosis although relapse does EWS-FLI1 and TMPRSS2-ERG by EAF and KI; ETV6-RUNX1 by happen in 20% of patients. The report from Borssen et al. is especially AM and KI. English grammar was checked by AM and EAF. intriguing since t(12; 21)(p13; q22) E/R fusion is associated with hTERT References promoter [164] methylation with short telomeres, and thus with more favorable prognosis of ALL. 1. Bister K, Nunn M, Moscovici C, Perbal B, Baluda M, et al. (1982) Acute leukemia viruses E26 and avian myeloblastosis virus have related transformation-specific RNA sequences but different genetic structures, gene products, and oncogenic properties. Current problems and future directions Proc Natl Acad Sci U S A 79: 3677-3681. [Crossref] ETS proteins are frequently activated in human cancers by 2. Moelling K, Pfaff E, Beug H, Beimling P, Bunte T, et al. (1985) DNA-binding activity translocation. To make GEMM for EWS, the EWS-FLI1 fusion is associated with purified proteins from AMV and E26 viruses and is temperature- transcripts express exclusively in mesenchymal stem cells to avoid its sensitive for E26 ts mutants. Cell 40: 983-990. [Crossref] expression in hematological tissues. When crossed with interferon 3. Metz T, Graf T (1991) Fusion of the nuclear oncoproteins v-Myb and v-Ets is required -inducible Mx1-Cre mice, activation of EWS-FLI1 resulted in the for the leukemogenicity of E26 virus. Cell 66: 95-105. [Crossref] rapid development of myeloid/erythroid leukemia characterized by 4. Findlay VJ, LaRue AC, Turner DP, Watson PM, Watson DK (2013) Understanding the expansion of mononuclear cells causing hepatosplenomegaly, severe role of ETS-mediated gene regulation in complex biological processes. Adv Cancer anemia, and death. Gene expression profiles of animals were highly Res 119: 1-61. [Crossref] similar to those of human Ewing’s sarcoma, suggesting that activation 5. Feldman RJ, Sementchenko VI, Watson DK (2003a) The epithelial-specific Ets of EWS-FLI1 was the primary event leading to disease in this model. factors occupy a unique position in defining epithelial proliferation, differentiation and carcinogenesis. Anticancer Res 23: 2125-2131. [Crossref] The Cre-inducible EWS-FLI1 mice provide a novel model system to study the contribution of this oncogene to malignant disease in vivo. 6. Feldman RJ, Sementchenko VI, Gayed M, Fraig MM, Watson DK (2003) Pdef Ink4a expression in human breast cancer is correlated with invasive potential and altered gene The disease is accelerated in p16 -null mice but not Arf-null mice expression. Cancer Res 63: 4626-4631. [Crossref] suggesting the critical role of p16INK4a in Ewing’s sarcoma. In ETS family, the ERG and ETV genes are frequently activated by translocation in 7. Fry EA, Inoue K (2018) ETS1 and ETS2 proteins in human cancer. Cancer Reports and Reviews. In press. human cancer; since the fusion protein often has nearly normal or normal functions of ERG, we speculate that overexpression of ERG 8. Sacchi N, Watson DK, Guerts van Kessel AH, Hagemeijer A, Kersey J, et al. (1986) Hu-ets-1 and Hu-ets-2 genes are transposed in acute leukemias with (4;11) and (8;21) proteins is essential for prostate cancer development. The prognostic translocations. Science 231: 379-382. [Crossref] value of TMPRSS2-ERG fusion in human PCa is still controversial; it seems that it is associated with intermediate survival outcomes second 9. Sacchi N, Cheng SV, Tanzi RE, Gusella JF, Drabkin HA, et al. (1988) The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia to p53 and PTEN inactivation. The prognostic value of TMPRSS2-ERG translocation (8;21). Genomics 3: 110-116. [Crossref] fusion will be determined in future prospective studies. 10. Nucifora G, Birn DJ, Erickson P, Gao J, LeBeau MM, et al. (1993) Detection of DNA In pediatric B-cell ALL, the translocation involving ETV6 rearrangements in the AML1 and ETO loci and of an AML1/ETO fusion mRNA in and RUNX1 are very common. It is believed that this is a favorable patients with t(8;21) . Blood 81: 883-888. [Crossref] prognostic factor. The fusion protein develops as an early event in 11. Miyoshi H, Kozu T, Shimizu K, Enomoto K, Maseki N, et al. (1993) The t(8;21) childhood ALL. CDKN2a/b, ETV6, PAX5, deletions, -6q, and +16 translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO J 12: 2715-2721. [Crossref] are among the earliest genetic aberrations in E/R(+) ALL; they are secondary events that contribute to the leukemic disease. Although 20% 12. Rao VN, Papas TS, Reddy ES (1987) , a human ets-related gene on chromosome 21: of patients suffer from late relapse, studies show that relapsed leukemia alternative splicing, polyadenylation, and translation. Science 237: 635-639. [Crossref] responds to chemotherapy with 5-year survival rate of more than 13. Rao VN, Modi WS, Drabkin HD, Patterson D, O’Brien SJ, et al. (1988) The human erg 80%, and thus it is believed that it is a favorable prognostic indicator. gene maps to chromosome 21, band q22: relationship to the 8; 21 translocation of acute myelogenous leukemia. Oncogene 3: 497-500. [Crossref] However, leukemia-free survival remains low for many patients after relapse and despite efforts to intensify therapeutic outcomes for these 14. Murakami K, Mavrothalassitis G, Bhat NK, Fisher RJ, Papas TS (1993) Human ERG- 2 protein is a phosphorylated DNA-binding protein--a distinct member of the ets children. The development of novel therapeutic approaches such as family. Oncogene 8: 1559-1566. [Crossref] anti-sense therapy or small molecule inhibitor to the chimeric gene holds great promise for the first-line treatment for patients with E/R(+) 15. Buchanan J, Tirado CA (2016) A t(16;21)(p11;q22) in Acute Myeloid Leukemia (AML) Resulting in Fusion of the FUS/TLS and ERG Genes: A Review of the Literature. J relapsed ALL. Assoc Genet Technol 42: 24-33. [Crossref] In any case of human cancer with ETS translocations, specific 16. Hibshoosh H, Lattes R (1997) Immunohistochemical and molecular genetic approaches therapy can be attempted to fusion proteins to eradicate tumor cells to soft tissue tumor diagnosis: a primer. Semin Oncol 24: 515-525. [Crossref] since they play critical roles in causing the neoplastic disease. 17. Acs B, Szarvas T, Szekely N, Nyirady P, Szasz AM1 (2015) Current State of ERG as Biomarker in Prostatic Adenocarcinoma. Curr Cancer Drug Targets 15: 643-651. Acknowledgements [Crossref] We thank all other members of Dr. Inoue’s lab for sharing 18. Berg KD (2016) The prognostic and predictive value of TMPRSS2-ERG gene fusion and ERG protein expression in prostate cancer biopsies. Dan Med J 63. [Crossref] unpublished research data. 19. Sanguedolce F, Cormio A, Brunelli M, D’Amuri A, Carrieri G, et al. (2016) Urine Financial support TMPRSS2: ERG Fusion Transcript as a Biomarker for Prostate Cancer: Literature Review. Clin Genitourin Cancer 14: 117-121. [Crossref]

K. Inoue was supported by NIH/NCI 2R01CA106314, ACS RSG- 20. Sundaresh A, Williams O (2017) Mechanism of ETV6-RUNX1 Leukemia. Adv Exp 07-207-01-MGO, and KG080179. Med Biol 962: 201-216. [Crossref]

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21. Sun C, Chang L, Zhu X (2017) Pathogenesis of ETV6/RUNX1-positive childhood 44. Kim S, Denny CT, Wisdom R (2006) Cooperative DNA binding with AP-1 proteins is acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 8: required for transformation by EWS-Ets fusion proteins. Mol Cell Biol 26: 2467-2478. 35445-35459. [Crossref] [Crossref]

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